Optimized tDCS for fibromyalgia: targeting the endogenous pain control system

针对纤维肌痛的优化 tDCS：针对内源性疼痛控制系统

• 批准号: 9756306
• 负责人: Felipe Fregni
• 金额: $ 42.86万
• 依托单位: SPAULDING REHABILITATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756306
• 关键词: Adverse effects; Aerobic Exercise; Affect; Analgesics; Brief Pain Inventory; Chronic; Clinical; Combined Modality Therapy; Control Groups; Coupled; Data; Development; Diagnosis; Dose; Effectiveness; Electroencephalography; Electrophysiology (science); Evolution; Exercise; Fibromyalgia; Future; Goals; Hyperalgesia; Individual; Insula of Reil; Intervention; Lead; Life; Light; Measurement; Measures; Mediating; Motor; Motor Cortex; Neuronal Plasticity; Pain; Pain intensity; Pain management; Patients; Personal Satisfaction; Physiologic pulse; Prediction of Response to Therapy; Prefrontal Cortex; Quality of life; Questionnaires; Randomized; Reporting; Secondary to; Sensory; Societies; Somatosensory Cortex; System; Techniques; Testing; Thalamic structure; Therapeutic Intervention; Time; Transcranial magnetic stimulation; Unemployment; active control; allodynia; base; central sensitization; chronic pain; cingulate cortex; clinical effect; conditioned pain modulation; conditioning; cost; design; fibromyalgia pain; fibromyalgia patients; improved; indexing; insight; intervention effect; neural network; neuroregulation; new therapeutic target; novel; novel therapeutics; pain outcome; pain reduction; pain relief; pain score; primary outcome; relating to nervous system; response; restoration; secondary analysis; treatment effect; treatment optimization; treatment strategy

1. ABSTRACT Fibromyalgia (FM) pain affects upwards of 5 million people in US annually and can have a considerable impact on patients’ quality of life and costs for the society (e.g., treatments or unemployment costs). Given the limited and variable effects of most of the therapeutic interventions for FM, there is an unmet clinical need for the development of novel interventions in FM. Recent evidence has suggested that FM pain can be related to deficits in pain endogenous regulatory control. In this context, our central hypothesis is that, to improve their efficacy, novel treatments of FM need to target specific neural networks associated with this endogenous pain regulatory system. Our rationale is based on studies showing that transcranial direct current stimulation (tDCS) of primary motor cortex is a powerful non-invasive neuromodulation technique of known to significantly modulate neural plasticity and alleviate chronic pain. Our group reported the first positive results of tDCS in FM in 2006. In order to optimize the treatment effects of motor cortex tDCS, we recently hypothesized that combining tDCS with aerobic exercise (AE) would increase its effects, given its enhanced modulatory effect of motor system engagement on endogenous pain system by combining two therapies. We conducted a preliminary trial testing this hypothesis and showed a beneficial effect of the combined treatment. This proposal was developed based on this preliminary data. Our specific aims are: (i) evaluate the effects of tDCS and aerobic exercise on endogenous pain control as assessed by temporal slow pain summation (TSPS) and conditioned pain modulation (CPM); (ii) determine the effect of these interventions on cortical markers of inhibitory control that are also affected in FM, such as intracortical inhibition as assessed by transcranial magnetic stimulation (TMS) and changes in thalamocortical dysrhythmia as assessed by EEG; (iii) assess whether engagement of the two main targets tested in this study – STS and CPM – are associated with changes in pain outcomes (e.g., Brief Pain Inventory and other clinical scales). Our main approach will be carried out using a randomized 2x2 mechanistic factorial controlled trial in 94 patients diagnosed with FM. Subjects will be randomized to one of four groups: tDCS and AE; sham tDCS and AE; active tDCS and nAE (non-AE= control intervention for AE); sham tDCS and nAE. The findings from this study will be significant as there is an unmet clinical need for the development of novel therapies in FM, particularly non-pharmacological ones, based on mechanistic approaches and target engagement. The extensive sensory and electrophysiological measurements that will be conducted with conditioned pain modulation and temporal slow pain summation, single- and paired-pulse transcranial magnetic stimulation, and quantitative electroencephalography will provide novel mechanistic insights that, independently of the main clinical aim, will be significant to future studies investigating novel pain therapies. Current treatments for FM have either limited efficacy or are associated with systemic adverse effects. From a clinical perspective, as secondary analysis, we will investigate the time evolution of pain scores (i.e., BPI) to understand the treatment dose-response in order to provide important insights for the design of future trials investigating the analgesic effects of tDCS. Finally, this proposal is novel given that this treatment is based on a neural target for pain control, the endogenous pain control system, and the results of this trial will not only bring a potential novel way of treating FM, by looking into the endogenous pain control, but will also shed light into pain mechanisms of FM and its relationship to a major modulator: the motor system.

1. 摘要 纤维肌痛 (FM) 疼痛每年影响美国超过 500 万人，并对患者的生活质量和社会成本（例如治疗或失业成本）产生相当大的影响。鉴于大多数 FM 治疗干预措施的效果有限且可变，因此开发新的 FM 干预措施的临床需求尚未得到满足。最近的证据表明，FM 疼痛可能与疼痛内源性调节控制缺陷有关。在这种情况下，我们的中心假设是，为了提高疗效，FM 的新疗法需要针对与这种内源性疼痛调节系统相关的特定神经网络。我们的理由基于研究表明初级运动皮层的经颅直流电刺激（tDCS）是一种强大的非侵入性神经调节技术，已知可以显着调节神经可塑性并减轻慢性疼痛。我们的小组于2006年报道了tDCS在FM中的第一个积极结果。为了优化运动皮层tDCS的治疗效果，我们最近假设将tDCS与有氧运动（AE）相结合会增加其效果，因为通过结合两种疗法可以增强运动系统参与对内源性疼痛系统的调节作用。我们进行了初步试验来检验这一假设，并显示了联合治疗的有益效果。该提案是根据这些初步数据制定的。我们的具体目标是：(i) 通过颞慢痛总和 (TSPS) 和条件性疼痛调节 (CPM) 评估 tDCS 和有氧运动对内源性疼痛控制的影响； (ii) 确定这些干预措施对抑制控制皮质标志物的影响，这些标志物在 FM 中也受到影响，例如通过经颅磁刺激 (TMS) 评估的皮质内抑制和通过脑电图评估的丘脑皮质节律障碍的变化； (iii) 评估本研究中测试的两个主要目标（STS 和 CPM）的参与是否与疼痛结果的变化相关（例如，简要疼痛量表和其他临床量表）。我们的主要方法将在 94 名诊断为 FM 的患者中使用随机 2x2 机械析因对照试验进行。受试者将被随机分配到四组之一：tDCS 和 AE；假 tDCS 和 AE；主动 tDCS 和 nAE（非 AE=AE 的控制干预）；假 tDCS 和 NAE。这项研究的结果将具有重要意义，因为基于机制方法和目标参与开发 FM 新型疗法，特别是非药物疗法，尚未得到满足的临床需求。将通过条件性疼痛调节和颞慢痛总和、单脉冲和成对脉冲经颅磁刺激以及定量脑电图进行广泛的感觉和电生理学测量，将提供新颖的机制见解，独立于主要临床目标，对于未来研究新型疼痛疗法的研究具有重要意义。目前的 FM 治疗要么疗效有限，要么与全身不良反应相关。从临床角度来看，作为二次分析，我们将研究疼痛评分（即 BPI）的时间演变，以了解治疗剂量反应，从而为未来研究 tDCS 镇痛效果的试验设计提供重要见解。最后，该提议是新颖的，因为该治疗基于疼痛控制的神经靶标，即内源性疼痛控制系统，并且该试验的结果不仅将通过研究内源性疼痛控制带来一种潜在的治疗 FM 的新方法，而且还将揭示 FM 的疼痛机制及其与主要调节器：运动系统的关系。